Cancer is a multifaceted disease that strikes millions every year. As there are many varieties of normally differentiated cell types, there is a large proportion of abnormalities that become clinically important in humans and animals. For example, melanoma is a particularly devastating type of cancer with a five-year survival rate projected to be less than 5%. There is only one single-agent drug approved for the treatment of melanoma; its rate of effectiveness is estimated at as low as about 10%.
In contrast, the onset of certain cancers has been traced to a missed apoptotic signal (Johnstone, R. W.; Ruefli, A. A.; Lowe, S. W. Cell 2002, 108, 153-164). In these cases, compounds that induce apoptosis (such as etoposide, doxorubicin, and camptothecin) have proven to be powerful chemotherapeutic agents. However, for a compound to be medicinally useful it is critical that this apoptotic induction be selective for cancer versus non-cancer cells. Indeed, it is rare to find compounds that have the selectivity needed to merit serious consideration as chemotherapeutic agents (Haskell, C. M. Cancer Treatment Ed.; W.B. Saunders Company, 62-87).
Apoptosis, or programmed cell death, is a highly conserved process used by multi-cellular organisms to rid themselves of unwanted or damaged cells (Blatt, N. B., Glick, G. D. Bioorg. Med. Chem. Lett. 2001, 9, 1371-1384; Newmeyer, D. D.; Ferguson-Miller, S. Cell 2003, 112, 481-490; Huang, Z. Chem. Biol. 2002, 9, 1059-1072). Hallmarks of apoptosis include cellular membrane blebbing, cleavage of certain nucleases and polymerases, and activation of cysteine proteases known as caspases. From a medicinal perspective, small molecules that either inhibit or induce apoptosis have significant therapeutic potential (Reed, J. C. Nat. Rev. Drug Dis. 2002, 1, 111-121; Makin, G.; Dive, C. Trends Mol. Med. 2003, 9, 251-255). Besides cancer, degenerative disorders such as Alzheimer's and Parkinson's diseases are thought to result from an aberrant increase in apoptosis (Hartmann, A. et al. Proc. Natl. Acad. Sci. 2000, 97, 2875-2880; Mattson, M. P. Nat. Rev. Mol. Cell Biol. 2000, 1, 120-129; Marx, J. Science 2001, 293, 2192-2194). In such cases, apoptotic inhibitors hold considerable medicinal promise.
Clearly there is a tremendous need to develop compositions and methods better able to address cancers. The identification of chemically-based libraries of compounds, individual compounds, combinations of compounds, and methods for applications in the treatment and study of cancer and the modulation of apoptosis are of significant value.